Nasal spray compositions

ABSTRACT

An aqueous nasal decongestant composition containing oxymatazoline is disclosed which does not contain mercurial preservatives.

BACKGROUND OF THE INVENTION

This invention relates to an aqueous, topical, nasal decongestantcomposition containing oxymetazoline or a pharmaceutically acceptablesalt thereof, an aqueous carrier which does not require undesirablemercurial anti-microbal agents.

Aqueous, topical, nasal decongestant compositions containingoxymetazoline hydrochloride, the longest acting nasal decongestantcurrently available, are applied to the nasal passages of mammalsespecially human beings to effect temporary relief of nasal congestionassociated with colds, hay fever and sinusitis.

It is known that one of the most common complaints of patients andconsumers that use nasal spray products is the drying and associatedstinging within the nasal cavity. Other common nasal product negativeattributes include odor and product taste. Additionally, due to thepropensity of nasal products to become microbially contaminated, the useof a two preservative ingredient formulation is preferred.

It is also well known that aromatic ingredients, such as menthol,camphor and eucalyptol are used to promote the opening, draining andsubsequent relief of sinus pressure in nasal spray products.Unfortunately, such ingredients are not soluble in water and require theaddition of solubilizers to the formulation. It is also unfortunate thatthe required amount and solubilizers, such as Polysorbate 80 and alcoholsolvents significantly adds to the associated unpleasant odor andstinging within the nasal cavity. It is also well known that theaddition of surfactants, such as Polysorbate 80 greatly reduces theantimicrobial activity of benzalkonium chloride. As a result of thismicrobial activity reduction in benzalkonium chloride, other well knownmercurial preservatives, such as thimerosal and phenyl mercuric acetateare reluctantly used.

A menthol flavored composition containing vapors of menthol, eucalyptoland camphor in addition to oxymetazoline hydrochloride and an aqueouscarrier is currently available as an OTC product under the tradenameAFRIN® Menthol Nasal Spray from Schering-Plough HealthCare Products,Liberty Corner, N.J. The aqueous carrier of this product containsbenzalkonium chloride, glycerine, phenylmercuric acetate, sorbitol,polysorbate 80 and water.

The use of mercurial preservatives, e.g. phenylmercuric acetate, innasal compositions, has been questioned and elimination of mercurialpreservatives is desirable.

We have surprisingly discovered that incorporation of an aromaticalcohol, e.g. benzyl alcohol and phenyl ethyl alcohol, in menthol typenasal sprays containing oxymetazoline allows removal of the undesirablemercurial preservatives from the nasal spray compositions.

It has been discovered that the incorporation of benzyl alcohol inmenthol type aromatic nasal sprays has generated benefits beyond whatwould be normally expected as "well known" within the formulation arts.It has been found that the characteristic odor of the aromatic alcoholsis effectively covered by the menthol type odor. This resulted in thedevelopment of a product with a pleasant aromatic odor. It has also beendiscovered that the addition of aromatic alcohols allowed for theunexpected and desired reduction, and or elimination of requiredsurfactants. As surfactants are also characterized as having anunpleasant odor this reduction cointributed to a pleasant product odor.Furthermore, it has been unexpectedly discovered that the lowersurfactant usage levels did not affect the microbial activity ofbenzalkonium chloride, allowing removal of mercurial preservatives andstill maintain a preservative system based on two ingredients.

SUMMARY OF THE INVENTION

The present invention provides an aqueous, topical nasal, decongestantcomposition comprising an amount of oxymetazoline or a pharmaceuticallyacceptable salt thereof sufficient to effect nasal decongestion and anaqueous carrier which is free of mercurial preservatives.

The present invention also provides an aqueous, flavored, topical nasaldecongestant composition comprising an amount of oxymetazoline or apharmaceutically acceptable salt thereof sufficient to effect nasaldecongestion and an aqueous carrier comprising:

70 to 90% by weight/volume of water;

0.10 to 5.00% by weight/volume of an aromatic alcohol;

0 to 0.3% by weight/volume of a non-mercurial anti-microbialpreservative

0 to 10% by weight/volume of a moisturizing agent;

0 to 0.10% by weight/volume of an antioxident;

0 to 2.00% by weight/volume of a surfactant;

0 to 0.75% by weight/volume of menthol;

0 to 0.15% by weight/volume of camphor;

0 to 0.15% by weight/volume of eucalyptol; and

a sufficient amount of a pharmaceutically acceptable buffer to maintainthe pH of the composition within the range of about 4.00-8.00;

and QS water.

The present invention further provides a method of treating nasalcongestion by administering to a nasal passage of a patient with nasalcongestion an aqueous, topical nasal decongestant composition of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel nasal compositions of the present invention containoxymetazoline and an aqueous carrier.

The amount of oxymetazoline or pharmaceutically acceptable salt thereoffound sufficient to effect nasal decongestion is in the range of about0.01% to about 0.1% by weight/volume of the topical nasal decongestantcomposition. Typically, 0.05% by weight/volume of oxymetazoline (as theHCl salt) is suitable for adults and children above five years of age.Oxymetazoline HCl is commercially available from Schering Labs.Kenilworth, N.J. See also The Merck Index. Tenth Edition, 1983 p. 6838.By the term "pharmaceutically acceptable salt" as used herein is meantthe acid addition salt formed by admixing oxymetazoline with apharmaceutically acceptable acid such as HCl, HF, H₂ SO₄, HNO₃, malonic,succinic, trifluoroacetic acids and the like.

The compositions of the present invention contain an aromatic alcoholselected from the group consisting of benzyl alcohol and phenyl ethylalcohol. The amount of aromatic alcohol present in the composition isfrom about 0.10 to 5.00% by weight/volume of the total composition.Ranges of 0.20-3.00% by weight/volume of the total composition areparticularly suitable, and a range of 0.25 to 1.00% by weight/volume ofthe total composition being most preferable.

The compositions of the present invention may contain a surfactant, e.g.polysorbate 80. The amount of surfactant present in the composition isfrom about 0 to 2.00% by weight/volume of the total composition. Rangesof 0 to 1.50% by weight/volume of the total composition are particularlysuitable, and a range of 0 to 1.25% by weight/volume of the totalcomposition being most preferable.

The compositions of the present invention may contain moisturizingagents, e.g. propylene glycol. The amount of moisturizing agent presentin the composition is from about 0 to 10.00% by weight/volume of thetotal composition. Ranges of 1.00 to 4.00% by weight/volume of the totalcomposition are particularly suitable, and a range of 1.5 to 3.50% byweight/volume of the total composition being most preferable.

The compositions of the present invention may contain an antioxidant,e.g. disodium EDTA. The amount of antioxident present in the compositionis from about 0 to 0.10% by weight/volume of the total composition.Ranges of 0.01 to 0.05% by weight/volume of the total composition areparticularly suitable, and a range of 0.015 to 0.030% by weight/volumeof the total composition being most preferable.

The compositions of the present invention contains at least oneantimicrobial preservative in the range of 0.01% to about 0.3% byweight/volume of the composition. Typical suitable preservativesfunction as antimicrobial agents and include the commercially availablepreservatives, e.g. benzalkonium chloride in the range of about 0.02 toabout 0.025% by weight/volume.

The compositions of the present invention also include pharmaceuticallyacceptable buffers sufficient to adjust and maintain the pH of thecompositions of the present invention in the range of about 4.0 to about8.0, preferably about 5.5 to about 7.0 and 6.25 to 6.75 being mostpreferable. Typically suitable buffers include citrate, phosphate andglycine.

The nasal spray compositions of the present invention is manufactured ina conventional manner by thoroughly mixing the ingredients at ambient orelevated temperatures in order to achieve solubility of ingredientswhere appropriate.

All percentages are by weight/volume. The definitions of componentswhose chemical composition is not immediately clear from the name used,such as "Polysorbate 80", may be found in the CTFA Cosmetic IngredientsDictionary, 4th Edition, 1991, published by Cosmetic Toiletry andFragrance Association, Inc., Washington, DC.

The following examples describe in detail the invention. It will beapparent to those skilled in the art that modifications may be practicedwithout departing from the purpose and intent of this disclosure.

EXAMPLE 1

An aromatic nasal spray formulated with 2.2% solubilizing agentrequiring a preservative system based on mercurial compounds to yieldsatisfactory microbial activity.

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sorbitol (70% solution)                                                                             5.7100                                                  Glycine USP (aminoacetic acid)                                                                      0.3747                                                  Benzalkonium chloride (17% solution)                                                                0.1169                                                  Polysorbate 80 NF (Tween 80)                                                                        2.2000                                                  L-Menthol USP         0.2000                                                  Camphor USP (synthetic)                                                                             0.0400                                                  Eucalyptol            0.0400                                                  Phenylmercuric Acetate                                                                              0.0024                                                  Oxymetazoline Hydrochloride USP                                                                     0.0500                                                  Water USP purified    QS                                                      ______________________________________                                    

EXAMPLE 2

A satisfactorily preserved mercurial free aromatic nasal spray isformulated with 1.0% Benzyl alcohol enabling a 43.2% reduction insolubilizing agent.

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        1.0000                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol USP  3.5000                                                  Polysorbate 80 NF (Tween 80)                                                                        1.2500                                                  L-Menthol USP         0.1750                                                  Camphor USP (Synthetic)                                                                             0.0300                                                  Eucalyptol            0.0300                                                  Oxymetazoline hydrochloride USP                                                                     0.0500                                                  Water USP purified    QS                                                      ______________________________________                                    

Method of Preparation

1. To any appropriate reaction container, add the following: sodiumphosphate monobasic, sodium phosphate dibasic, disodium EDTA, benzylalcohol and oxymetazoline hydrochloride to 70% of the water at atemperature of 50° C. Continue mixing the aqueous mixture while coolingto 30° C.

2. In a separate container, add with mixing the following: menthol,camphor, eucalyptol and Polysorbate 80 and continue to mix until all isin solution.

3. In a separate container, add 10% of the water and the propyleneglycol and mix the solution at 30° C. for at least 5 minutes.

4. Transfer the solution of step 2 to the solution of step 3 and mix forat least 5 minutes.

5. Transfer the contents of step 4 into the aqueous mixture of step 1.

6. While mixing, add the benzalkonium chloride 17% solution to theaqueous mixture of step 5 and mix for at least 5 minutes.

7. Adjust the final batch volume with water, mix until uniform and thenfilter.

EXAMPLE 3

A satisfactorily preserved mercurial free aromatic nasal spray isformulated with 0.25% Benzyl alcohol enabling a 90.9% reduction insolubilizing agent.

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        0.2500                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol USP  1.5000                                                  Polysorbate 80 (Tween 80)                                                                           0.1500                                                  L-Menthol USP         0.0900                                                  Camphor USP (Synthetic)                                                                             0.0300                                                  Eucalyptol            0.0300                                                  Oxymetazoline hydrochloride                                                                         0.0500                                                  Water USP purified    QS                                                      ______________________________________                                    

The procedure for preparation of this composition is as described inExample 2.

EXAMPLE 4

A satisfactorily preserved mercurial free aromatic nasal spray isformulated with 0.25% Benzyl alcohol enabling a 93.2% reduction insolubilizing agent.

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        0.2500                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol USP  1.5000                                                  Polysorbate 80 (Tween 80)                                                                           0.1500                                                  L-Menthol USP         0.0400                                                  Camphor USP (Synthetic)                                                                             0.0100                                                  Eucalyptol            0.0100                                                  Oxymetazoline hydrochloride                                                                         0.0500                                                  Water USP purified    QS                                                      ______________________________________                                    

The procedure for preparation of this composition is as described inExample 2.

EXAMPLE 5

A satisfactorily preserved mercurial free aromatic nasal spray isformulated with 0.25% Benzyl alcohol and reduced aromatic ingredientsenabling a 100.0% reduction in solubilizing agent.

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        0.2500                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol USP  1.5000                                                  Eucalyptol            0.0300                                                  Oxymetazoline hydrochloride                                                                         0.0500                                                  Water USP purified    QS                                                      ______________________________________                                    

The procedure for preparation of this composition is as described inExample 2.

We claim:
 1. An aqueous, topical, nasal decongestant compositioncomprising an amount of oxymetazoline or a pharmaceutically acceptablesalt thereof sufficient to effect nasal decongestion and an aqueouscarrier comprising:70 to 90% by weight/volume of water; 0.10 to 5.00% byweight/volume of an aromatic alcohol; 0.01 to 0.3% by weight/volume of anon-mercurial antimicrobial preservative; 0 to 10% by weight/volume of amoisturizing agent; 0 to 0.10% by weight/volume of an antioxidant; 0 to2.00% by weight/volume of a surfactant; 0 to 0.75% by weight/volume ofmenthol; 0 to 0.15% by weight/volume of camphor; 0 to 0.15% byweight/volume of eucalyptol; a sufficient amount of a pharmaceuticallyacceptable buffer to maintain the pH of the composition within the rangeof about 4.00 to 8.00; and QS water,said composition being free ofmercurial antimicrobial preservatives.
 2. The composition of claim 1comprising:0.05% by weight/volume of oxymetazoline; 80% by weight/volumeof water; 0.25-1.00% by weight/volume of an aromatic alcohol; 0.02 to0.025% by weight/volume of a non-mercurial antimicrobial preservative;1.5 to 3.5% by weight/volume of a moisturizing agent; 0.015 to 0.03% byweight/volume of an antioxidant; 0.0 to 1.25% by weight/volume of asurfactant; 0.10 to 0.20% by weight/volume of menthol; 0.020 to 0.035%by weight/volume of camphor; 0.020 to 0.075% by weight/volume ofeucalyptol; a sufficient amount of a pharmaceutically acceptable bufferto maintain the pH of the composition within the range of about 6.25 to6.75; and QS water.
 3. The composition of claim 1 wherein the aromaticalcohol is benzyl alcohol; the non-mercurial anti-microbial preservativeis benzalkonium chloride; the moisturizing agent is propylene glycol;the antioxidant is disodium EDTA; and the surfactant is polysorbate 80.4. The composition of claim 3 comprising:

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        1.0000                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol USP  3.5000                                                  Polysorbate 80        1.2500                                                  L-Menthol USP         0.1750                                                  Camphor USP           0.0300                                                  Eucalyptol            0.0300                                                  Oxymetazoline hydrochloride USP                                                                     0.0500                                                  Water USP purified    QS.                                                     ______________________________________                                    


5. The composition of claim 3 comprising:

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        0.2500                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol      1.5000                                                  Polysorbate 80        1.1500                                                  L-Menthol USP         0.0900                                                  Camphor USP           0.0300                                                  Eucalyptol            0.0300                                                  Oxymetazoline hydrochloride USP                                                                     0.0500                                                  Water USP purified    QS.                                                     ______________________________________                                    


6. The composition of claim 3 comprising:

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        0.2500                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol      1.5000                                                  Polysorbate 80 (Tween 80)                                                                           1.1500                                                  L-Menthol USP         0.0400                                                  Camphor USP (Synthetic)                                                                             0.0100                                                  Eucalyptol            0.0100                                                  Oxymetazoline hydrochloride USP                                                                     0.0500                                                  Water USP purified    QS.                                                     ______________________________________                                    


7. The composition of claim 3 comprising:

    ______________________________________                                        Ingredients           % Wt/Vol                                                ______________________________________                                        Water USP purified    80.0000                                                 Sodium phosphate monobasic                                                                          0.5525                                                  Sodium phosphate dibasic                                                                            0.0975                                                  Disodium EDTA         0.0200                                                  Benzyl alcohol        0.2500                                                  Benzalkonium chloride (17% solution)                                                                0.1177                                                  Propylene glycol USP  1.5000                                                  Eucalyptol            0.0300                                                  Oxymetazoline hydrochloride                                                                         0.0500                                                  Water USP purified    QS.                                                     ______________________________________                                    


8. A method of treating nasal congestion which comprises administeringto a nasal passage of a patient with nasal congestion an aqueous, nasal,decongestant composition of claim 1.